1. Field of the Invention
The present invention is directed to a novel process for producing intermediates useful in the synthesis of 1-.beta.-alkyl carbapenems.
2. Description of the Prior Art
A wide variety of carbapenems, such as the natural fermentation product thienamycin (Formula I), have been reported in the patent and scientific literature as having exceptional antibacterial activity. ##STR2##
However, researchers attempting to develop thienamycin have encountered two problems, namely: (1) the compound is very difficult to ferment and isolate, and (2) the product is very unstable, such that it reacts with itself and decomposes. To circumvent these problems, carbapenem derivatives have been prepared which possess excellent stability and antibacterial spectra.
One such group of derivatives currently being investigated is the 1-.beta.-methyl carbapenems of the formula: ##STR3##
wherein R.sup.1 is hydrogen or a conventional hydroxy-protecting group; and
R.sup.2 and R.sup.3 are independently selected from the group consisting of substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; spirocycloalkyl having 3-6 carbon atoms; phenyl; aralkyl, aralkenyl and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the hereto atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen and sulfur atoms and the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the alkyl moieities of the above-recited substituents have 1-6 carbon atoms.
Recently reported synthetic schemes for producing 1-.beta.-methyl carbapenems of Formula II, such as those of Shih et al., Heterocycles, volume 21, no. 1, pages 29-40 (1984), proceed through diazo intermediates of the formula ##STR4## from which the 1-.beta.-methyl carbapenems can be formed easily and in high yield. Unfortunately, however, these schemes require numerous other intermediates and time consuming steps to produce the above diazo intermediate, each of which increases the process time and decreases the overall yield. Accordingly, there is a need for a fast, simple, high yield, stereoselective process for producing diazo intermediates which can be readily converted to 1-.beta.-alkyl carbapenems.
It follows, therefore, that precursors are needed which facilitate fast and stereoselective preparation of the above-described diazo intermediates.
One such precursor is a 4-chloroazetidinone of the formula ##STR5##
wherein R.sup.1 is hydrogen or a conventional hydroxy-protecting group. However, such 4-chloroazetidinones which are unsubstituted on the 1-position nitrogen have heretofore been regarded as too unstable to produce or impossible to isolate. Accordingly, there is a need for fast, simple, high yield processes for producing 4-chloroazetidinone precursors which are unsubstituted on the 1-position nitrogen.